Treprostinil, also known as UT-15, is a known compound disclosed in U.S. Pat. No. 4,306,075 in example 33. Treprostinil is a synthetic analog of epoprostenol, a prostaglandin F1. The activities ascribed to the various compounds of this patent include inhibition of smooth muscle cell proliferation, inhibition of platelet aggregation, inhibition of cytokine secretion, reduction of gastric secretion, vasodialation and bronchodilation.
U.S. Pat. No. 5,153,222 discloses the use of Treprostinil and related compounds to treat pulmonary hypertension. U.S. Pat. No. 6,054,486 discloses the use of Treprostinil and related compounds to treat peripheral vascular disease, such as peripheral arterial occlusive disease and intermittent claudication. Patterson et al., Amer. J of Cardiology, 75: 26A–33A (1995), have shown vasodilator effects of Treprostinil in patients with class III or class IV heart failure.
Clapp et al., Am. J. Respir. Cell. Mol. Biol., 26(2): 194–201 (2002), have shown that Treprostinil inhibits proliferation of human pulmonary arterial smooth muscle cells. Raychaudhuri et al,. J. Biol. Chem., 277(36): 33344–8 (2002), have disclosed that Treprostinil inhibits inflammatory cytokine (tumor necrosis factor-α, interleukin-1β, interleukin-6, and granulocyte macrophage colony-stimulating factor) secretion and gene expression by human alveolar macrophages.
Healthy kidney functions includes producing urine, maintaining water balance by removing excess fluid from the body, removing waste products (e.g., urea and creatinine) from the blood, maintaining normal blood chemistry (e.g., proper concentrations of sodium, potassium, chloride, calcium, magnesium, sulfate, phosphate and hydrogen in extracellular fluid), and producing hormones, such as renin (helps regulate blood pressure), erythropoietin (helps maintain proper blood volume by stimulating the production of red blood cells) and calcitriol (helps facilitate calcium absorption from food).
Mesangial proliferative glomerulonephritis is a uncommon kidney disorder characterized by swelling of the body (edema) and blood in the urine. It is caused by inflammation of an internal kidney structure (glomerulus), involving an increase in number of certain cells of the glomerular capillaries, known as mesangial cells. The mechanism that triggers the disorder is unknown, but it is believed to be some type of immune response (see e.g., www.nlm.nih.gov/medlineplus/ency/article/000821.htm), because inflammation of the glomeruli is associated with deposits of antibodies. During this kidney malfunction, the mesangial cells increase in size and number, which give the glomeruli a lumpy appearance (see e.g., www.nlm.nih.gov/medlineplus/ency/article/000487.htm).
Diabetic nephropathy is the most common cause of renal failure in the United States and other developed countries. Mesangial expansion contributes to glomerular basement membrane thickening in diabetic nephropathy leading to glomerulosclerosis. The mechanism contributing to these physiologic changes are directly related to the hyperglycemia and micorvascular dysfunction. Van Dijk, C. & Berl, T., 2004 “Pathogenesis of Diabetic Nephropathy. Reviews in Endocrine and Metabolic Disorders; 5: 237–248. See e.g., www.nlm.nih.gov/medlineplus/ency/article/000494.htm.